coss数据分析.pdf
J Neurosurg/Volume 118/January 2013 25J Neurosurg 118:2533,2013AANS,2013Complete occlusion of the ICA by atherosclerotic disease causes approximately 15%25%of isch-emic strokes in the carotid artery distribution.22,26,37 Patients treated with medical therapy have a 7%10%risk of recurrent stroke per year for any stroke and a 5%8%risk per year for ipsilateral ischemic stroke dur-ing the first 2 years after ICA occlusion.17,18,20,21 Internal carotid artery occlusion causes an estimated 61,000 first-ever strokes per year in the US,1,6,14,22,26,37,39 an incidence more than twice the annual occurrence of ruptured intra-cranial aneurysms.5 Superficial temporal arterymiddle cerebral artery anastomosis was developed to improve hemodynamics distal to an occluded artery.11,38,41 The In-ternational Study of Extracranial-to-Intracranial Arterial Anastomosis(EC-IC bypass trial)tested the usefulness Surgical results of the Carotid Occlusion Surgery StudyClinical articleRobeRt L.GRubb JR.,M.D.,1,2 WiLLiaM J.PoWeRs,M.D.,4 WiLLiaM R.CLaRke,Ph.D.,5 toM o.ViDeen,Ph.D.,2,3 haRoLD P.aDaMs JR.,M.D.,6 anD CoLin P.DeRDeyn,M.D.,13 foR the CaRotiD oCCLusion suRGeRy stuDy inVestiGatoRsDepartments of 1Neurological Surgery,2Radiology,and 3Neurology,Washington University School of Medicine in St.Louis,Missouri;4Department of Neurology,University of North Carolina School of Medicine,Chapel Hill,North Carolina;5Clinical Trials Statistics and Data Management Center,University of Iowa College of Public Health;and 6Department of Neurology,University of Iowa Carver School of Medicine,Iowa City,Iowa Object.The Carotid Occlusion Surgery Study(COSS)was conducted to determine if superficial temporal ar-terymiddle cerebral artery(STA-MCA)bypass,when added to the best medical therapy,would reduce subsequent ipsilateral stroke in patients with complete internal carotid artery(ICA)occlusion and an elevated oxygen extraction fraction(OEF)in the cerebral hemisphere distal to the occlusion.A recent publication documented the methodol-ogy of the COSS in detail and briefly outlined the major findings of the trial.The surgical results of the COSS are described in detail in this report.Methods.The COSS was a prospective,parallel-group,1:1 randomized,open-label,blinded-adjudication treat-ment trial.Participants,who had angiographically demonstrated complete occlusion of the ICA causing either a transient ischemic attack or ischemic stroke within 120 days and hemodynamic cerebral ischemia indicated by an increased OEF measured by PET,were randomized to either surgical or medical treatment.One hundred ninety-five patients were randomized:97 to the surgical group and 98 to the medical group.The surgical patients underwent an STA-MCA cortical branch anastomosis.Results.In the intention-to-treat analysis,the 2-year rates for the primary end point were 21%for the surgical group and 22.7%for the medical group(p=0.78,log-rank test).Fourteen(15%)of the 93 patients who had under-gone an arterial bypass had a primary end point ipsilateral hemispheric stroke in the 30-day postoperative period,12 within 2 days after surgery.The STA-MCA arterial bypass patency rate was 98%at the 30-day postoperative visit and 96%at the last follow-up examination.The STA-MCA arterial bypass markedly improved,although it did not normalize,the level of elevated OEF in the symptomatic cerebral hemisphere.Five surgically treated and 1 nonsur-gically treated patients in the surgical group had a primary end point ipsilateral hemispheric stroke after the 30-day postoperative period.No baseline characteristics or intraoperative variables revealed those who would experience a procedure-related stroke.Conclusions.Despite excellent bypass graft patency and improved cerebral hemodynamics,STA-MCA anasto-mosis did not provide an overall benefit regarding ipsilateral 2-year stroke recurrence,mainly because of a much bet-ter than expected stroke recurrence rate(22.7%)in the medical group,but also because of a significant postoperative stroke rate(15%).Clinical trial registration no.:NCT00029146.(http:/thejns.org/doi/abs/10.3171/2012.9.JNS12551)key WoRDs symptomaticoccludedinternalcarotidartery superficialtemporalarterymiddlecerebralarteryanastomosis impairedcerebralhemodynamics positronemissiontomography oxygenextractionfraction randomizedtrial vasculardisorders25Abbreviations used in the paper:COSS=Carotid Occlusion Surgery Study;EC-IC=extracranial-intracranial;EC-IC bypass trial=The International Study of Extracranial-to-Intracranial Arte-rial Anastomosis;ICA=internal carotid artery;IRB=institutional review board;MCA=middle cerebral artery;NINDS=National Institute of Neurological Disorders and Stroke;OA=occipital artery;OA-MCA=occipital arterymiddle cerebral artery;OEF=oxygen extraction fraction;POD=postoperative day;STA-MCA=superficial temporal arterymiddle cerebral artery;TIA=transient ischemic attack.See the corresponding editorial in this issue,pp 2024.R.L.Grubb Jr.et al.26 J Neurosurg/Volume 118/January 2013of STA-MCA bypass surgery as a prophylaxis against stroke.13 STA-MCA bypass was not effective in prevent-ing subsequent stroke as compared with the best medi-cal therapy in any group of patients,including the 808 patients with symptomatic complete occlusion of the ICA.Based on results of this trial,EC-IC arterial bypass was generally abandoned as a treatment for symptomatic complete ICA occlusion.After the trial,several groups criticized the results on multiple grounds,2,8,35 including the inability to identify and separately analyze a subgroup of patients with impaired cerebral hemodynamics due to occlusive cerebrovascular disease in whom surgical re-vascularization might be more beneficial.8Since then,advances in neuroimaging have made it possible to determine the hemodynamic effects of ICA occlusion in individual patients.9,10,16,20,24,40 The stron-gest evidence for an association between cerebral he-modynamic impairment and stroke was provided by the St.Louis Carotid Occlusion Study(STLCOS).16 In this blinded prospective study,investigators found that severe hemodynamic failure,manifested by an elevated OEF in the cerebral hemisphere distal to complete ICA occlusion,was an independent predictor of subsequent stroke in symptomatic medically treated patients.The STA-MCA arterial bypass surgery has been shown to improve cere-bral hemodynamics distal to an occluded ICA.4,15,17,29,28,33The Carotid Occlusion Surgery Study(COSS)was a prospective,parallel-group,1:1 randomized,open-label,blinded-adjudication treatment trial designed to test the hypothesis that STA-MCA anastomosis,when combined with the best medical therapy,could reduce by 40%the subsequent occurrence of ipsilateral ischemic stroke at 2 years in patients with recent symptomatic ICA occlusion and ipsilateral increased OEF as measured by PET.The trial design and analysis as well as primary results have already been reported.27 The primary end points in the surgical group were 1)all stroke and death from surgery through 30 days postoperatively plus 2)ipsilateral hemi-spheric ischemic stroke within 2 years of randomization.The primary end points in the nonsurgical group were 1)all stroke and death from randomization through 30 days plus 2)ipsilateral hemispheric ischemic stroke within 2 years of randomization.All primary end points were ipsilateral ischemic strokes.Based on an intent-to-treat analysis,2-year rates for ipsilateral ischemic stroke were 21.0%(20 events,95%CI 12.8%29.2%)for the 97 par-ticipants in the surgical group and 22.7%(20 events,95%CI 13.9%31.6%)for the 98 patients in the nonsurgical group(p=0.78,z-test;difference=1.7%;95%CI-10.4%to 13.8%).The initial report of results for the COSS trial27 had only a brief description of the major findings,which are reviewed in the current article.In addition,we include a large amount of unpublished data about the STA-MCA bypass procedures done in this trial,which we believe should be widely available to vascular neurosurgeons.Reports of the original EC-IC bypass trial3,13 contained few details about the 652 STA-MCA bypasses performed in that study.These data are no longer available,which is a major loss for vascular neurosurgery.MethodsInformed ConsentStudy participants provided written informed con-sent according to local IRB regulations and study pro-tocol requirements(COSS Clinical Coordinating Center IRB approval:Washington University in St.Louis Human Research Protection Office#01-370 and University of North Carolina IRB Approval#3071020;US FDA IND#62,657).This clinical trial(no.NCT00029146)was reg-istered with ClinicalTrials.gov(http:/clinicaltrials.gov).Surgical ProcedureThe EC-IC arterial bypass procedure used in the COSS trial was a standard STA-MCA cortical branch anastomosis.12,25,30,41 If the STA was not suitable for anas-tomosis to the MCA,the OA could be used in place of the STA.All surgical patients were placed on 81 or 325 mg of aspirin daily prior to the bypass procedure.All other perioperative issues,such as anticonvulsants,antibiotics,choice of anesthetic agents,intraoperative hemodynamic monitoring,and perioperative fluid loading,were left to the discretion of the operating surgeon.The STA-MCA cortical branch anastomosis was done using the best STA branch and the best MCA cortical branch.Only one anas-tomosis was done in each patient.Patients with an“un-suitable”STA(diameter 1 mm)were excluded from the study.Details of the surgical technique used for the STA-MCA anastomosis,such as the use of running or inter-rupted 10-0 Prolene or nylon sutures,a straight or ellipti-cal incision in the MCA cortical branch,and preparation of the STA graft,were left to the discretion of the operat-ing surgeon.During and immediately following the sur-gical procedure,data concerning anesthesia techniques,intraoperative blood pressures,cerebral monitoring,and technical aspects of the bypass procedure were recorded and saved for analysis.After surgery,all patients were left on 81 or 325 mg of aspirin for at least 30 days.Thereafter,when deemed appropriate by the neurosurgeon,patients were returned to the antithrombotic treatment preferred by their physicians.Intraoperative assessment of STA-MCA bypass patency was performed using Doppler ul-trasound examination and/or cerebral angiography.The first follow-up visit was 3035 days after randomization.All surgical participants underwent repeat PET scanning 3060 days postoperatively.Subsequent follow-up visits occurred at 3-month intervals after randomization un-til 24 months or the end of the trial.Doppler ultrasound examination was used to determine postoperative STA-MCA bypass patency at follow-up visits.Surgical CertificationSurgeons were certified for the study 1)by attend-ing an initial training workshop in St.Louis where vid-eotaped instruction was viewed and surgical practice of microvascular anastomosis was performed on frozen cadaver heads and live rat carotid arteries,or 2)by dem-onstrating at least 80%bypass graft patency and 10%incidence of stroke and death at 1 month in at least 10 consecutive STA-MCA bypass surgeries.Surgeons with fewer than 10 STA-MCA bypass cases available for re-J Neurosurg/Volume 118/January 2013Surgical results of the Carotid Occlusion Surgery Study27view received provisional certification to perform the STA-MCA bypass in an enrolled patient under the super-vision of the principal neurosurgical investigator for the trial or a designated neurosurgeon with extensive STA-MCA bypass experience.Further Cerebrovascular ProceduresBoth the nonsurgical and surgical patients were pro-hibited from undergoing any additional surgical proce-dures after the STA-MCA arterial bypass that might alter cerebral hemodynamics or affect stroke risk,except for a carotid endarterectomy performed for the development of symptomatic contralateral stenosis of the ICA.Statistical AnalysisCategorical variables are displayed as counts and rates,and continuous variables are displayed as means standard deviations.Univariate analyses were used to compare baseline values and intraoperative variables be-tween those who had a stroke within 2 days of surgery and those who did not.We compared the 2 groups using gen-eralized Fisher exact tests for categorical variables,t-tests for continuous variables that were approximately normal-ly distributed,and Wilcoxon rank-sum tests for variables that were not normally distributed(noted in tables).Even though there were a large number of such comparisons,we did not adjust p values for the multiplicity.For the comparison of 2-year outcomes between surgeons who were department or division chairs and those who were not,Kaplan-Meier methods were used to describe the dis-tribution of time to primary event for each group.The log-rank test was used to compare the 2 distributions.ResultsThirty different surgeons(Appendix)performed 92 STA-MCA bypasses and 1 OA-MCA bypass at a median of 6 days(interquartile range 113 days)after randomiza-tion to the surgical group.Four participants randomized to the surgical group did not undergo surgery.No strokes occurred during the time between randomization and sur-gery.The bypass patency rate was excellent:98%(88 of 90 patients with patency data)at the 30-day postoperative visit.One patient died in the postoperative period,and graft patency data were not recorded in 2 other patients at the 30-day follow-up visit.At the last follow-up visit during which STA-MCA arterial bypass patency was as-sessed(mean 605 270 days,range 281596 days),the graft patency rate was 96%(86 of 90 patients with pa-tency data).The mean OEF ratio in the surgical group improved from 1.258 0.14 at baseline(93 patients)to 1.109 0.101 at the 30-to 60-day postoperative repeat PET(87 patients).Comparing the 87 patients who had both a preoperative and a postoperative PET scan,the mean OEF ratio improved from 1.254 0.135 to 1.109 0.101(p 0.0001).In a previous study,the upper limit of the OEF ratio calculated using similar methods in 18 normal patients was 1.062.16 Twenty-nine percent(25 of 87)of the postoperative PET scans in the COSS had an OEF ratio within the normal range.Fourteen(15%)of the 93 patients who underwent an arterial bypass had a primary end point ipsilateral hemi-spheric stroke in the 30-day postoperative period.Twelve of the 14 postoperative ipsilateral hemispheric strokes oc-curred within the first 2 days following surgery;the other 2 cases occurred 5 and 15 days after surgery.The oc-currence of 2 strokes more than 2 days after surgery,but within 30 days,was a pattern identical to that observed in the nonsurgical group of 98 patients,which had 2 ipsilat-eral strokes within 30 days of randomization.Of the 14 strokes occurring within the 30-day post-operative period,2 were disabling at the last follow-up(Barthel Index 12)and 1 was fatal.The patient who died in the postoperative period had 2 ipsilateral strokes on the day of surgery,had a vertebrobasilar artery dis-tribution stroke on POD 1,and died o
